Phylos is developing in vitro RNA-protein fusion technology for the rapid identification, selection and, engineering of proteins (including antibody mimics) with unique characteristics. As an alterative to antibodies or their fragments, we are investigating the targeting of small protein scaffolds that may be more suitable for pharmacological use. By selecting rare proteins from very large libraries (>10[13] members), we are able to select binders with a higher affinity (i.e. Kd<10[-9]) than those obtained using smaller libraries (e.g. phage display or in vivo monoclonal antibody selection). The lower dosing required by such high affinity binders should have clear pharmacological benefits. In addition, the smaller size of the binders (8.5 kD vs 150 kD for antibodies) may allow deeper penetration into tissues and tumors. The additional potential to "evolve" proteins by amplification under error-prone conditions, coupled with positive or negative selection pressure, provides additional flexibility in drug design. During Phase I of the program, a novel scaffold was identified and demonstrated for the generation of high-affinity binders to targets that are involved in angiogenesis. During Phase II of the program, we will use these binders to establish: (1) their activity in a variety of cell-based assays; (2) their anti-angiogenic and anti-tumor activities in animal tumor models; and (3) optimize their pharmacological characteristics to identify a lead compound for use in the clinic. PROPOSED COMMERCIAL APPLICATION: This technology will help to validate the use of a novel class of therapeutic drugs that will potentially compete and augment the use of monoclonal antibody therapy for cancer as well as many other diseases. It will simultaneously speed the process of identifying high-affinity antigen binders as well as develop more clinically useful antibody mimic proteins that may have enhanced therapeutic qualities and lower production costs.